D-galactose (D-gal) has been widely used to induce mimetic aging in various animals. In the current study, we used Melatonin and R-?-lipoic acid to explore their antioxidant and anti-aging effect in D-gal induced mimetic aging in male Musca domestica. In this study, we finalized the doses of Melatonin and R-?-lipoic acid upon chronic administration (20 days). Our results confirmed that these antioxidant administrations significantly improved the ROS generated by decreasing the levels of AOPPs, and MDA levels in aging houseflies. Melatonin and R-?-lipoic acid administration elevated the activities of SOD and proteins levels which are suppressed by aging. Our results signify that both Melatonin and R-?-lipoic acid effectively alleviated oxidative stress and improved protein levels in D-Gal induced aged houseflies.